D614G, B.1.1.7, B.1.351, P.1. These codes represent drastic changes in the evolution of SARS-CoV-2, reflecting the adaptive nature and evolutionary brilliance of viruses. But what does their emergence mean for us as a global community?
Before beginning, I’d like to note a few things regarding terms and concepts surrounding viruses and their mutations.
First, in both media and scientific literature, the terms “strain”, “lineage”, and “variant” are used interchangeably to describe the same concept.
Second, the spike protein of SARS-CoV-2 is located on the surface of the virus, and spans the entire plasma membrane. This is the primary site of adaptive mutations, for a few different reasons. Unlike other proteins on the surface of the virus, the spike protein’s primary purpose is to interact with and induce entry to the host cell by activating a specific receptor on the surface. The spike protein is also what is called an antigen–the part that is recognized by the specific immune system (circulating antibodies), triggering a specialized attack against it. For these reasons, spike protein mutations are evolutionarily favorable if:
- they increase the virus’ ability to enter the cell,
- they increase the ability of the virus to be transmitted from person to person, or
- they ‘camouflage’ the virus against antibodies (both human and monoclonal), so that the immune system fails to mount an attack against it.
Third, it is important to understand that all viruses mutate, multiple times a month, and SARS-CoV-2 is no exception. There are countless mutations (especially in a disease this prolific), but only a few rise to the forefront in terms of prevalence, transmissibility, and immune evasion. The following named variants are the ones that have been recognized as variants of concern (VOC) by the CDC.
For those interested in the specific molecular mechanisms of mutation for the three most recently discovered variants, the CDC has a great summary here of the specific protein modifications and RNA sequences that confer the unique characteristics of each lineage. You will find that many RNA sequences leading to higher rates of transmission are conserved among these variants, showing the clear evolutionary advantage of those sequences over that of the baseline variant(s).
It’s also notable that all variants have evidence to suggest increased viral loads in patients.
The SARS-CoV-2 virus, like other members of the coronavirus family, is a master of camouflage and adaptation, with its first recorded functional variant (D614G) occurring almost immediately after its emergence in Wuhan, China. The information that we have regarding the interactions with the host immune system and the outcomes relating to these variants remains murky, with only a few months of data collected on the newer UK (B.1.1.7), South African (B.1.351), and Brazilian (P.1) variants.
With second waves being reported in many countries, and the rollout of multiple vaccines showing varied efficacies, it is important to remain vigilant in monitoring the development of more evasive SARS-CoV-2 variants. It is always a possibility to see an emergence of vaccine-resistant strains, and for that reason, despite vaccine rollout, it remains critical to minimize possible exposures and protect our communities from outbreaks.
Alongside COVID-19 in the family of coronaviruses, there are two other respiratory diseases. Middle east respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS). These coronaviruses have both been around for many years, yet never had a licensed vaccine to combat them, despite the fact that MERS has a 35% death rate and SARS has a 9.7% death rate. Why were no vaccines developed against these deadly viruses, yet such a rapid vaccine response was mounted against COVID-19?
There are a couple lines of reasoning suggested for this difficulty or unwillingness to develop vaccines against MERS or SARS, since pharmaceutical companies give unclear answers to this inquiry. One thing is for sure: the development of vaccines against these diseases is not profitable, since the outbreaks happen at random intervals and transmissibility is low, with relatively few patients. The financial drive to develop a COVID-19 vaccine was huge, with an entire global population at the mercy of this virus.
Continuing that line of reasoning, due to the zoonotic nature of coronaviruses, the risk of developing a vaccine which failed to protect against emerging variants may have outweighed the financial benefit. MERS and SARS silently rest in reservoir animal hosts in between human outbreaks, mutating, evolving, becoming more deadly or transmissible, and when outbreaks happen, the mutated variants often do not respond to treatments or prevention in the same way. Zoonotic viruses are infamous for their ability to jump between species and in doing so, mutate dramatically. SARS-CoV-2 is absolutely not an exception.
It is essential to be informed about secondary outbreaks of COVID-19, zoonotic back-and-forth transmissions, and spike protein mutations that could have a cumulative effect on how well patients respond to treatment and vaccines. We have already seen one significant zoonotic leap, from humans, to seagulls, to mink and back to humans, which caused a huge response in the global community. Entire mink populations in the affected countries were culled, with 17 million mink being killed in Denmark alone as a preventative measure against potentially deadly mutations. This drastic response to species-hopping is due to the extremely high risk of possibly more deadly variants developing in this way, as they have been shown to do in MERS and SARS.
For these reasons, it’s essential to monitor emerging variants of SARS-CoV-2 for changes in clinical presentation, mortality, transmission, or immune evasion.
The first mutation in the genome of SARS-CoV-2 was D614G, a spike protein mutation. D614G was a swift adaptation to the new human hosts after leaping from an animal host, increasing the transmission rate between people and quickly overtaking the original Wuhan strain both in China and globally. This variant easily dominated due to its increased ability to infect. Natural selection is often cold, and this is one example of that fact; the more hosts that the virus can infect, the greater its evolutionary success.
On December 14th, 2020, the UK reported that a sequence of SARS-CoV-2 RNA showed a new mutation, also in the spike protein gene. This variant, which is now the dominating variant in the UK, is the B.1.1.7 variant. This variant also demonstrated an unsettling leap in infectivity, such that smaller exposures were sufficient to lead to illness, and has been reported in 52 countries. The strength of this variant is the same driving force that caused D614G to dominate: B.1.1.7 is thought to be around 50% more transmissible than the baseline variant, based on the limited data available since it was discovered in December 2020. We do not have sufficient data for conclusive percentages, but there is evidence that B.1.1.7 is associated with a higher death rate, according to the CDC.
There have been 3,037 B.1.1.7 cases in the United States so far, in 49 states.
The UK performs more viral genetic sequencing than any other country in the world, quickly surpassing all other countries in COVID-19 sequencing. It’s absolutely possible that this variant had been circulating long before UK scientists came across it.
The B.1.351 variant, also known as the South African variant, was discovered on December 18, 2020, but samples dating back to October 2020 have been shown to be of this lineage. The B.1.351 variant has two particular strengths: both the increased transmissibility mutation (also found in the B.1.1.7 variant) as well as the mutation linked to immune evasion are present. Immune evasion is the ability of the virus to camouflage itself from antibodies, making this lineage of particular concern in vaccine efficacy. Since vaccines rely on spike protein recognition by antibodies to function, patients with the B.1.351 variant still respond to the Pfizer and Moderna vaccines, but that they are less effective in protection length and total response against this variant.
81 cases of the B.1.351 strain have been reported in the USA so far.
There are two new, single-shot vaccines undergoing preliminary tests that show protection against this variant (Novavax and Janssen). The arms race against SARS-CoV-2 mutations has already begun, and B.1.351 is already the dominating variant in many provinces in South Africa, and has now been reported in 20 countries. In fact, travel bans from many African countries, including the Congo and Tanzania, have been instituted in the UK. The USA has also banned travel from South Africa in an attempt to control this particularly concerning variant.
At the end of January 2021, the P.1 variant, or Brazil variant, was first identified at a Tokyo airport in four travelers from Brazil. This strain, with the most limited data of all variants, is thought to be more transmissible than any other. It also contains a mutation that may confer increased immune evasion, again threatening the efficacy of vaccines and antibody treatments against it.
In Manaus, Brazil, over 75% of the population had already been infected with and recovered from COVID-19; yet with the emergence of the P.1 variant, many were re-infected, showing its blatant disregard for antibodies developed against earlier strains. This is a significant threat, since it indicates previous infection or monoclonal antibody treatments offer little to no protection against this variant.
This quickly made the P.1 variant a variant of concern, with travel bans from Brazil being instituted in many countries. This variant is too new to be addressed by vaccine manufacturers, but one Brazilian study indicated that the Sinovac vaccine is effective against P.1, where Pfizer and Moderna fall short.
As of March 3, 2021, the first P.1 patient in the USA was identified in a Chicago hospital.
The CDC has provided little information or statistics on this brand-new variant, but in coming months new data should shed light on this shadowy new threat to the COVID-19 arms race. Complacency is easy to come across in a world where, after a year of lockdown, mRNA vaccine technology finally represents a light at the end of the pandemic tunnel. However, vigilance in protecting our communities, limiting travel and exposures, and wearing masks in public to reduce transmission remain critical until herd immunity is achieved and treatment-resistant variants are controlled.
The coronaviruses are clever and adaptive, and their global success as a species is no mistake. Where SARS and MERS have high death rates and low transmission rates, SARS-CoV-2 steadily increased transmission, with long asymptomatic infectious periods and increased viral loads, easily outdoing others in the family. It retains the critical ability of its less-sophisticated cousins to change its spike protein conformation to fool adaptive immune systems and facilitate transmission, and to leap back and forth from animal to human to develop deadly mutations.
As much as we all want to get back to our normal lives, interactions, and routines, it’s essential to remember that natural selection and cold, abiotic viruses still regularly outsmart us. We all would be wise to regard SARS-CoV-2 as the formidable opponent that it is, and continue to take serious precaution. The more we limit the transmission of the virus, the less it can mutate and become more resistant to treatment and immune responses.